17-4937769-G-A

Variant names:

• chr17-4937769-G-A
• NM_003562.5:c.917C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003562.5(SLC25A11):​c.917C>T​(p.Ala306Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC25A11 NM_003562.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.43

Genes affected

SLC25A11 (HGNC:10981): (solute carrier family 25 member 11) The oxoglutarate/malate carrier transports 2-oxoglutarate across the inner membranes of mitochondria in an electroneutral exchange for malate or other dicarboxylic acids (summary by Iacobazzi et al., 1992 [PubMed 1457818]).[supplied by OMIM, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116288334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC25A11	NM_003562.5	c.917C>T	p.Ala306Val	missense_variant	Exon 8 of 8	ENST00000225665.12	NP_003553.2
SLC25A11	NM_001165417.2	c.884C>T	p.Ala295Val	missense_variant	Exon 8 of 8		NP_001158889.1
SLC25A11	NM_001165418.2	c.764C>T	p.Ala255Val	missense_variant	Exon 7 of 7		NP_001158890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC25A11	ENST00000225665.12	c.917C>T	p.Ala306Val	missense_variant	Exon 8 of 8	1	NM_003562.5	ENSP00000225665.7
SLC25A11	ENST00000576951.1	c.884C>T	p.Ala295Val	missense_variant	Exon 8 of 8	5		ENSP00000458993.1
SLC25A11	ENST00000544061.6	c.764C>T	p.Ala255Val	missense_variant	Exon 7 of 7	3		ENSP00000440804.2
SLC25A11	ENST00000574710.1	n.1724C>T		non_coding_transcript_exon_variant	Exon 6 of 6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 306 of the SLC25A11 protein (p.Ala306Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SLC25A11-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SLC25A11 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Benign	0.91
DEOGEN2	Benign	0.33	T;.;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	N;N;.
REVEL	Benign	0.20
Sift	Benign	0.46	T;T;.
Sift4G	Benign	0.50	T;T;.
Polyphen		0.011	B;.;.
Vest4		0.13
MutPred		0.55		Gain of methylation at K305 (P = 0.0449);.;.;
MVP		0.47
MPC		0.95
ClinPred		0.21	T
GERP RS		3.5
Varity_R		0.027
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-4841064;